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TGF-β Inhibitor Potentiates Osimertinib-Induced Anti-Tumor Immunity in Egfr-Mutant Lung Cancer

Tadahiro Kuribayashi1, Jun Nishimura1, Sachi Okawa1

  • 1Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Cancer Science
|February 27, 2026
PubMed

Insights

Combining TGF-β inhibitors with osimertinib enhances antitumor immunity in EGFR-mutated non-small cell lung cancer. This novel strategy boosts T cell response and warrants clinical investigation for improved lung cancer treatment.

Area of Science:

  • Oncology
  • Immunology
  • Pharmacology

Background:

  • Immunotherapy for EGFR-mutated NSCLC faces challenges due to immunosuppressive cytokines like TGF-β induced by EGFR-TKIs.
  • EGFR-TKIs can paradoxically increase TGF-β, potentially limiting their effectiveness in non-small cell lung cancer.
  • Targeting TGF-β alongside EGFR inhibition may overcome treatment resistance in EGFR-mutated NSCLC.

Purpose of the Study:

  • To investigate if TGF-β inhibition can enhance osimertinib-induced antitumor immunity in a mouse model of EGFR-mutated lung cancer.
  • To evaluate the efficacy of combining osimertinib with TGF-β inhibitors (nintedanib or vactosertib) in vivo and in vitro.
  • To analyze the impact of combination therapy on the tumor microenvironment and immune cell populations.

Main Methods:

  • Utilized a syngeneic mouse model of EGFR-mutated lung cancer (subcutaneous tumor xenografts).
  • Assessed antitumor effects of osimertinib combined with nintedanib (indirect TGF-β inhibitor) or vactosertib (direct TGF-β inhibitor).
  • Analyzed tumor microenvironment changes via immunohistochemistry, western blot, and flow cytometry.

Main Results:

  • Combination therapy with osimertinib and nintedanib significantly enhanced antitumor effects compared to osimertinib monotherapy in vivo; no additive effect observed in vitro.
  • Osimertinib upregulated TGF-β expression; combination therapy decreased TGF-β and SMAD2/3 expression.
  • Combination therapy increased effector T cells and Granzyme B+ areas while decreasing CD206+ cells, indicating enhanced anti-tumor immunity.

Conclusions:

  • Combination of osimertinib with TGF-β inhibitors (nintedanib or vactosertib) potentiates osimertinib-induced antitumor immunity in EGFR-mutated NSCLC.
  • This combination strategy modulates the tumor microenvironment, promoting an anti-tumor immune response.
  • Findings support further clinical investigation of osimertinib and TGF-β inhibitor combinations for EGFR-mutated NSCLC treatment.
Keywords:
EGFRTGF‐βlung cancernintedanibosimertinib

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